The FOXP1-ABCG2 axis promotes the proliferation of cancer stem cells and induces chemoresistance in pancreatic cancer

Abstract

Pancreatic cancer is an aggressive disease with low survival and high recurrence rates. A major obstacle in treating pancreatic cancer is the frequent development of chemoresistance to the standard therapeutic drug, gemcitabine. One mechanism by which pancreatic cancer develops chemoresistance is through the proliferation of cancer stem cells (CSC). However, the mechanisms regulating stemness in chemoresistant tumors remain unclear. Here, we found that the expression of the transcription factor Forkhead Box P1 (FOXP1) was elevated in chemoresistant pancreatic cancer and crucial for establishing CSC characteristics. Silencing FOXP1 reduced the expressions of stemness-associated genes and diminished the formation of both spheroids and colonies, highlighting the crucial role of FOXP1 in regulating stemness in chemoresistant tumor cells. Mechanistically, we discovered that FOXP1 regulates the expression of ATP-binding cassette superfamily G member 2 (ABCG2), which induces the efflux of gemcitabine. Knockdown of FOXP1 reduced the expression of ABCG2, resulting in decreased proliferation and increased sensitivity to gemcitabine. Moreover, the inhibition of FOXP1 in orthotopic mouse models reduced tumor growth and proliferation, and enhanced sensitivity to gemcitabine. Together, our data reveal FOXP1 as a potent oncogene that promotes CSC growth in chemoresistant pancreatic cancer.